DESCRIPTION (Applicant's Description Verbatim): The M-CSF receptor, Fms, is a tyrosine kinase growth factor receptor expressed primarily in the monocyte-macrophage lineage of hematopoietic cell development. The molecular signals transmitted within susceptible cells by the activated Fms contribute to the development of cells toward mature macrophages. Homologues of Fms are expressed throughout the various stages of hematopoiesis where they regulate the development of distinct lineages and/or phases of progenitor cell growth and maturation. For example, Kit is expressed in progenitor cells and mature mast cells, Flt3 is broadly expressed in progenitor cell populations, and Flt I (also called KDR) may be expressed in stem cells. Thus, Fms may be considered the prototypical receptor for investigations of the signaling mechanism by these other tyrosine kinase growth factor receptors. The analyses of Fms signaling are more amenable to experimentation, and the results may be mechanistically relevant to the other receptors. We have been interested in the M-CSF-induced molecular signals that contribute to growth and differentiation, and how , both signals are integrated and regulated by Fms. Recent data indicate that multifunctional scaffolding proteins link the receptor to downstream signals. These proteins are called Gab-family members (exemplified by Gabl, Gab2, and Gab3), and the research results from the Drosophilahomologue, DOS, suggests they are necessary for development. We propose to investigate the molecular role of these proteins in Fms signaling using both biochemical analyses of protein signaling interactions in cell lines and genetic studies in Gab-knockout mice. These studies will be extended to look for additional Gab-family members in early stem/progenitor cells. Overall, the results of these experiments will describe new signaling mechanisms that may be useful for understanding the normal and abnormal development of blood cells and their diseases.